Is DDHD1 p.His889= (c.2667C>T) pathogenic?

DDHD1 p.His889= (c.2667C>T) is classified Likely benign in DDHD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-11). Ultra-rare (popmax 0.0165%, mid); Associated with hereditary spastic paraplegia 28.

What condition is associated with DDHD1 p.His889= (c.2667C>T)?

DDHD1 p.His889= (c.2667C>T) is associated with hereditary spastic paraplegia 28 (ClinVar).

How common is DDHD1 p.His889= (c.2667C>T) in the general population?

DDHD1 p.His889= (c.2667C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Autosomal recessive spastic paraplegia type 28 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

DDHD1 p.His889=

c.2667C>T · rs774873200 · VCV2771081

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

hereditary spastic paraplegia 28

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.8	GERP -3.2
Overall
CADD	5.492	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,052 alleles

Filtering AF 0.00208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00261% 42/1,610,480 alleles · ultra-rare exomes 33/1,458,708 · genomes 9/151,772 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,052
Finnishnot grpmax-eligible	0.00314%	31,891
European (non-Finnish)	0.00289%	34,654
South Asian	0.00221%	45,316
Admixed American	0.00168%	59,652
Remaining individualsnot grpmax-eligible	0.0016%	62,370
African / African-American	0.00134%	74,674

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DDHD1
Protein: p.His889=
Coding: c.2667C>T
MANE Select: NM_001160148
dbSNP: rs774873200
Type: single nucleotide variant
Location: chr14:53046804 (GRCh38)
Gene constraint: LOEUF 0.642 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 67.11

Full DDHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 28 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive spastic paraplegia type 28 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood, Infancy

Similar variants

DDHD1 p.His889Tyr Uncertain significance ★ ⚠ same residue
DDHD1 p.Ala193Val Uncertain significance ★★ ⚠ same condition
DDHD1 p.Ala94Pro Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg204Trp Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg288His Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg554Gln Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg570Gln Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg588Gln Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ddhd1-p-his889 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown